Increased permeability or hyperpermeability of the gut mucosal barrier is thought to play a role in several disorders and conditions such as bowel related diseases, autoimmune diseases, allergies, cancers, type 2 diabetes, obesity, depression, anxiety, and many others. For this reason, there has been an increased interest in understanding the role of the gut mucosal barrier dysfunction in the pathogenesis of many conditions targeting the gastrointestinal tract (GI) in mammals.
Under normal conditions, the gut mucosal barrier acts as a selective barrier permitting the absorption of nutrients, electrolytes and water and preventing the exposure to detrimental macromolecules, micro-organisms, dietary and microbial antigens (e.g. food allergens). The gut mucosal barrier is essentially composed of a layer of mucus and an underlying layer epithelial cells (referred to herein as ‘gut epithelial cells’). The gut epithelial cells are tightly linked to each other by so-called ‘tight junctions’, which are basically ‘physical joints’ between the membranes of two gut epithelial cells. Maintenance of the gut mucosal barrier, particularly maintenance of the physical integrity of the gut epithelial cell layer (i.e. keeping the junctions between cell tight), is crucial for protection of the host against the migration of pathogenic micro-organisms, antigens, and other undesirable agents from the intestine to the blood stream.
The gut mucosal barrier is also heavily colonized by approximately 1012-1014 commensal microorganisms, mainly anaerobic or microaerophilic bacteria, most of which live in symbiosis with their host. These bacteria are beneficial to their host in many ways. They provide protection against pathogenic bacteria and serve a nutritional role in their host by synthesizing vitamin K and some of the components of the vitamin B complex. Further, the gut mucosal barrier has evolved a complex ‘gut mucosal immune system’ for distinguishing between commensal (i.e. beneficial bacteria) and pathogenic bacteria and other detrimental agents. The gut mucosal immune system is an integral part of the gut mucosal barrier, and comprises lymphoid tissues and specialized immune cells (i.e. lymphocytes and plasma cells), which are scattered widely throughout the gut mucosal barrier. One of the microorganisms that naturally colonizes the mucosa of healthy subjects is the mucin-degrading Akkermansia muciniphila, which has been shown to increase the intestinal barrier function (Everard et al., PNAS 110 (2013) 9066-71; Reunanen et al., Appl Environ Microbiol Mar. 20, 2015), and thereby impact diseases associated with impaired gut barrier function.
Under certain circumstances, the gut mucosal barrier may be vulnerable to a wide variety of infectious organisms or agents, which are normally not able to cross the mucosal gut barrier but nevertheless manage to cross it (e.g. through gaps resulting from loose tight junctions between gut epithelia cells). Organisms or other agents that cross the gut mucosal barrier may cause diseases or other undesirable conditions (e.g. allergies) in the host. Examples of such diseases include obesity, metabolic syndrome, insulin-deficiency or insulin-resistance related disorders, type 2 diabetes, type 1 diabetes, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), glucose intolerance, abnormal lipid metabolism, atherosclerosis, hypertension, cardiac pathology, stroke, non-alcoholic fatty liver disease, alcoholic fatty liver disease, hyperglycemia, hepatic steatosis, dyslipidaemias, dysfunction of the immune system associated with obesity (weight gain), allergy, asthma, autism, parkinson's disease, multiple sclerosis, neurodegenerative diseases, depression, other diseases related to compromised barrier function, wound healing, behavioural disorders, alcohol dependence, cardiovascular diseases, high cholesterol, elevated triglycerides, atherosclerosis, sleep apnoea, osteoarthritis, gallbladder disease, and cancer.
Conversely, diseases such as those mentioned above as well as other conditions such as food allergies, immaturity of the gut, e.g., due to a baby being born prematurely, exposure to radiation, chemotherapy and/or toxins, autoimmune disorders, malnutrition, sepsis, and the like, may alter the physical integrity of the gut mucosal barrier (i.e. cause loosening of the tight junctions between the gut epithelial cells), which in turn may allow undesirable micro-organism or other agents to cross the host gut mucosal barrier.
Several vaccines and/or antibodies targeted against such micro-organisms or agents have been developed over the years. However, the success of such approach is mitigated as several micro-organisms or agents cannot be effectively targeted or eradicated with vaccines or antibodies.
Other approaches, which aim at preventing detrimental micro-organisms and other agents to cross the host's gut mucosal barrier in the first place and/or aim at preventing hyperpermeability of the gut mucosal barrier, have also been explored. For instance, compositions comprising glutamic acid have been developed to prevent and/or treat conditions associated with hyperpermeability of the gut mucosal barrier (WO 01/58283). Other substances including spermine and spermidine and precursors thereof, have also been used for the same purpose (Dorhout et al (1997). British J. Nutrition, pages 639-654). Preparations comprising arabinoxylan for promoting beneficial effects on the GI bacteria living in the vicinity of the gut mucosal barrier, have also been developed for the purpose of modulating the gut mucosal barrier (US2012/0230955).
It is an object of the present invention to provide agents and/or compositions comprising such agents, which are suitable for maintaining and/or restoring and/or increasing the physical integrity of the gut mucosal barrier and/or preventing hyperpermeability of the gut mucosal barrier in a mammal (e.g. human), and/or for maintaining and/or restoring and/or improving glucose and/or cholesterol and/or triglyceride homeostasis in a mammal, and preferably thereby prevent or treat diseases or conditions that are associated with suboptimal permeability of the gut mucosal barrier and/or glucose and/or cholesterol and/or triglyceride homeostasis imbalance in said mammal. Alternatively or additionally, it is an object of the present invention to provide agents and/or compositions comprising such agents, which are suitable for modulating and/or promoting the gut mucosal immune system function in a mammal.